Abstract
Background/Aim: The Renin–Angiotensin system (RAS) induces immunosuppression in the tumor microenvironment, and RAS inhibitors (RASi) improve the tumor immune microenvironment. We evaluated the impact of RASi on the efficacy anti-programmed cell death-1/Ligand-1 (anti-PD-1/PD-L1) antibodies. Patients and Methods: This retrospective study analyzed non-small cell lung cancer (NSCLC) patients who received anti-PD-1/PD-L1 antibodies monotherapy as second- or later-line treatment. We classified patients into those with or without use of RASi. Results: A total of 256 NSCLC patients were included and 37 patients used RASi. The median PFS of patients treated with RASi was significantly longer than that of patients treated without (HR=0.59, 95%CI=0.40-0.88). The median OS of patients treated with RASi tended to be longer than that of patients treated without (HR=0.71, 95%CI=0.45-1.11). Conclusion: The use of RASi was associated with a significantly longer PFS in NSCLC patients treated with anti-PD-1/PD-L1 antibodies. RASi use may enhance the efficacy of anti-PD-1/PD-L1 antibodies.
- Renin–angiotensin system inhibitors
- non-small cell lung cancer
- anti-programmed cell death 1/ligand-1 antibodies
- immunotherapy
Lung cancer is the leading cause of cancer death worldwide. Non-small cell lung cancer (NSCLC) accounts for about 85% of lung cancers. However, anti-programmed cell death-1/Ligand-1 (anti-PD-1/PD-L1) antibodies have improved the prognosis of NSCLC patients without oncogenic driver mutations. Nivolumab, pembrolizumab, and atezolizumab improved overall survival (OS) compared with docetaxel in pretreated NSCLC patients (1). Pembrolizumab prolonged OS in untreated NSCLC patients with positive PD-L1 expression compared with platinum-based chemotherapy (2, 3). Anti-PD-1/PD-L1 antibodies combined with chemotherapy improved progression-free survival (PFS) and OS compared with chemotherapy alone in untreated NSCLC patients with any PD-L1 expression (4-7). However, only some patients showed a long-term survival. Therefore, new strategies to enhance anti-PD-1/PD-L1 antibodies are needed.
Medicines against common diseases such as gastritis, esophagitis, diabetes mellitus, and even hypertension [e.g., Renin-Angiotensin system inhibitors (RASi) including angiotensin-converting enzyme inhibitors (ACEi) and Angiotensin-II receptor blockers (ARB)] have been reported to have immunomodulatory effects (8-10). In the tumor microenvironment, RAS is expressed in cancer-associated fibroblasts, macrophages, and cancer cells (11). Recent studies showed that, in the tumor immune microenvironment, RAS induces immunosuppression while RASi improves it (10, 12). However, the association between RASi use and the efficacy of immunotherapy has not been fully investigated. Therefore, we evaluated the impact of RASi on the efficacy of anti-PD-1/PD-L1 antibodies in NSCLC patients.
Patients and Methods
Patients and data collection. We retrospectively reviewed the electronic medical records of consecutive NSCLC patients who received anti-PD-1/PD-L1 antibody monotherapy as second- or later-line treatment at the Cancer Institute Hospital, Japanese Foundation for Cancer Research (Tokyo, Japan) between December 2015 and January 2020.
Patients received nivolumab (3 mg/kg of body weight or 240 mg) every 2 weeks, or pembrolizumab (200 mg) every 3 weeks, or atezolizumab (1,200 mg) every 3 weeks. We collected clinical data including age, sex, Eastern Cooperative Oncology Group performance status (PS), smoking status, tumor histology type, Epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangement status, PD-L1 tumor proportion score, number of previous chemotherapeutic regimens, RASi administration, calcium channel blockers (CCB) administration, complications with hypertension, or history of heart diseases. Patients who were diagnosed with hypertension by attending physicians and treated with antihypertensive agents were defined as hypertensive patients. RASi included enalapril, imidapril, azilsartan, candesartan, irbesartan, losartan, olmesartan, telmisartan, and valsartan. CCB included amlodipine, azelnidipine, benidipine cilnidipine, diltiazem, nicorandil, and nifedipine. We divided the patients by hypertension status, RASi and CCB administration at the time of initiation of anti-PD-1/PD-L1 antibody monotherapy. Moreover, we divided patients with hypertension according to RASi administration. We compared PFS and OS of anti-PD-1/PD-L1 antibody monotherapy between different groups. We performed a computed tomography (CT) at 6-10 weeks in clinical practice. Tumor response to anti-PD-1/PD-L1 antibody monotherapy on CT was assessed in accordance with the Response Evaluation Criteria in Solid Tumors 1.1. PFS was defined as the period between the initiation of anti-PD-1/PD-L1 antibody monotherapy and the date of disease progression or death from any cause. OS was defined as the period between the initiation of anti-PD-1/PD-L1 antibody monotherapy and the date of death from any cause. The study protocol was reviewed and approved by the Ethics Committee of the Cancer Institute Hospital, Japanese Foundation for Cancer Research (approval number 2020-1101). Informed consent of using the clinical data for this study was obtained by the method of opt-out on the website from the patients according to instructions of the Ethics Committee.
Statistical analysis. Continuous variables were compared between two groups using Mann-Whitney’s U-test. Discontinuous variables between two groups were compared using Fisher’s exact test. Kaplan-Meier curves of PFS and OS were generated, and the log-rank test was used to assess the difference between the different groups. Hazard ratios and associated 95% confidence intervals were calculated using a Cox proportional hazards model. Possible factors associated with PFS were identified by univariate Cox hazards models. All significant factors identified in the univariate analysis were tested in the multivariate Cox regression analysis. A p-value <0.05 was considered statistically significant. We performed all statistical analyses using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria).
Results
A total of 256 NSCLC patients were analyzed. The median length of follow-up was 27.0 months (95%CI=20.3-35.0 months) (Kaplan–Meier estimate). Patient characteristics are shown in Table I. The median age was 67 (27-83) years, and 72% of the patients were male. Of the 79 hypertensive patients, 40, 17, 19, and 3 patients were administered CCB without RASi, RASi without CCB, CCB and RASi, and other antihypertensive agents without RASi and CCB, respectively. Thirty-seven patients used RASi and anti-PD-1/PD-L1 antibodies simultaneously. Of these, only one patient received RASi for chronic heart failure without hypertension. CCB was used more in patients treated with RASi than in those without. The patients treated with RASi were significantly older than those treated without (p=0.025).
Patient characteristics.
There was no significant difference in PFS according to the presence of hypertension (Figure 1A). The PFS of patients treated with CCB was not significantly different from that of those treated without (Figure 1B). The median PFS of patients treated with RASi was significantly longer than in patients treated without (6.0 vs. 2.2 months; 95%CI=1.9-3.0 vs. 2.1-12.0 months; p=0.008; HR=0.59, 95%CI=0.40-0.88) (Figure 1C). In subgroup analysis of the hypertensive patients, PFS was significantly longer in patients treated with RASi than in those treated without (Figure 1D). Multivariate Cox regression analysis of sex, performance status (PS), smoking status, Epidermal growth factor receptor/anaplastic large-cell lymphoma kinase (EGFR/ALK) status, treatment line, and RASi use showed that PS of 0 or 1, EGFR/ALK-negative and RASi use were significantly associated with a longer PFS (Table II).
Kaplan–Meier curves showing progression-free survival (PFS); (A) Patients with hypertension (HT) versus patients without HT, (B) Patients with calcium channel blocker (CCB) use versus patients without CCB use, (C) Patients with renin–angiotensin system inhibitors (RASi) use versus patients without RASi use, (D) Patients with RASi use versus patients without RASi use in the patients with HT. HR: Hazard ratio; CI: confidence interval.
Cox regression analysis for progression free survival.
There was no significant difference in OS between hypertensive and non-hypertensive patients (Figure 2A). The OS of patients treated with CCB was not significantly different from that of patients treated without (Figure 2B). The median OS of patients treated with RASi was longer than in those treated without, though not statistically significant (22.6 vs. 14.7 months; 95%CI=10.6-36.4 vs. 11.4-17.8 months; p=0.131; HR=0.71, 95%CI=0.45-1.11) (Figure 2C). In the hypertensive patients, OS tended to be longer in patients treated with RASi (Figure 2D). Multivariate Cox regression analysis of PS, EGFR/ALK status, and treatment line showed that a PS of 0 or 1 was significantly associated with a longer OS (Table III).
Kaplan–Meier curves showing overall survival (OS); (A) Patients with hypertension (HT) versus patients without HT, (B) Patients with calcium channel blocker (CCB) use versus patients without CCB use, (C) Patients with renin–angiotensin system inhibitors (RASi) use versus patients without RASi use, (D) Patients with RASi use versus patients without RASi use in the patients with HT. HR: Hazard ratio; CI: confidence interval; NR: not reached.
Cox regression analysis for overall survival.
Discussion
In this study, RASi use improved PFS of patients who received anti-PD-1/PD-L1 antibodies. PFS was significantly longer in patients treated with RASi than in those treated without. Conversely, CCB use was not significantly associated with PFS. These results showed that RAS inhibition may enhance the efficacy of anti-PD-1/PD-L1 antibody.
RASi use has been reported to reduce cancer incidence and mortality (13). In lung cancer patients, RASi use has been associated with a lower rate of lymph node metastasis (14). However, these studies included few patients treated with anti-PD-1/PD-L1 antibodies because of their historical background. RASi use was significantly associated with a longer OS in NSCLC patients who received platinum-based chemotherapy (15). In another study, RASi use was significantly associated with a longer PFS in NSCLC patients treated with chemotherapy and EGFR-tyrosine kinase inhibitors (16). Unlike in our study, a subgroup analysis of hypertensive patients was not performed. Few studies have investigated the association between RASi use and the efficacy of anti-PD-1/PD-L1 antibodies.
Experiments revealed that RAS expression in cancer cells and endothelial cells plays important roles in tumor cell proliferation, apoptosis, vascularization, and metastasis (11). Angiotensin-II induces cell proliferation by binding to Angiotensin-II receptors in cancer cells. Angiotensin-II activates the intracellular cascade of protein kinases associated with growth factor stimulation including EGFR (17). Angiotensin-II also promotes tumor angiogenesis by up-regulating the expression of vascular endothelial growth factor (VEGF) (18). RAS components are also expressed in most immune cells (19). RAS is activated in macrophages, myeloid-derived suppressor cells, and fibroblasts and induces immunosuppression in the tumor microenvironment (10). ARB has been reported to decrease the production of immunosuppressive factors such as interleukin-6, interleukin-10, and VEGF and down-regulate the expression of immunosuppressive factors such as chemokine ligand 12 and nitric oxide synthase 2 in the tumor microenvironment (10). Another study showed that ACEi increased CD3+ T cell infiltration into the tumor and up-regulated PD-1 expression on both the CD8+ and CD4–CD8– tumor-infiltrating cells (12). These results support the positive effect of RASi on the efficacy of anti-PD-1/PD-L1 antibodies.
This study has several limitations. Its retrospective design and small sample size made selection bias inevitable. The treatment line was not uniform. However, it was not significantly associated with PFS and OS. The PD-L1 tumor proportion score was evaluated in only 25% of the patients. The patient characteristics were not uniform between those treated with or without RASi. Hypertension may have impacted some clinical outcomes. However, even if we focused on hypertensive patients, RASi use was associated with a significantly longer PFS of patients treated with anti-PD-1/PD-L1 antibodies.
Conclusion
In conclusion, RASi use was associated with a significantly longer PFS in NSCLC patients treated with anti-PD-1/PD-L1 antibody monotherapy. RASi use may enhance the efficacy of anti-PD-1/PD-L1 antibody.
Acknowledgements
The Authors would like to thank Editage (www.editage.com) for English language editing.
Footnotes
Authors’ Contributions
Study concept and design: TT, NY, MN. Acquisition and analysis of data and statistical analysis: TT, NY, HY, RM, SO, RT, HS, YA, RA, KU, SK, MN. Interpretation of data and drafting of the manuscript: TT, NY, HY, RM, SO, RT, HS, YA, RA, KU, SK, MS, AG, MN. Critical revision of the manuscript for important intellectual content: TT, NY, MS, AG, MN. Study supervision: MN. All Authors approved the final version of the manuscript and agreed to be accountable for all aspects of the work.
Conflicts of Interest
MN received honoraria from Ono Pharmaceutical, Bristol Myers Squibb, Pfizer, Chugai Pharmaceutical, Eli Lilly, Taiho Pharmaceutical, AstraZeneca, Boehringer-Ingelheim, MSD, Novartis; and received research funding from MSD, Novartis, Ono Pharmaceutical, Chugai Pharmaceutical, Bristol Myers Squibb, Taiho Pharmaceutical, Eli Lilly, AstraZeneca, Pfizer, Astellas; and had consulting/advisory roles for Novartis, Daiichi Sankyo Healthcare, Taiho Pharmaceutical, Bristol Myers Squibb, Boehringer-Ingelheim, Ono Pharmaceutical, Eli Lilly, Chugai Pharmaceutical, AstraZeneca, Merck Serono, MSD, Pfizer. AG has received honoraria from Ono Pharmaceutical, Bristol Myers Squibb, Pfizer, Chugai Pharmaceutical, Taiho Pharmaceutical, Daiichi Sankyo Healthcare, KYORIN Pharmaceutical, Accuray Japan, Boehringer-Ingelheim, MSD, AstraZeneca, Kyowa Kirin, Otsuka Pharmaceutical, Eisai; and received research funding from Nippon Kayaku. MS has received honoraria from Ono Pharmaceutical, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Taiho Pharmaceutical, AstraZeneca, Boehringer-Ingelheim, MSD; and received research funding from Taiho Pharmaceutical, Chugai Pharmaceutical, Boehringer-Ingelheim. NY has received honoraria from Ono Pharmaceutical, Taiho Pharmaceutical, MSD, Novartis, Bayer Yakuhin, and had consulting/advisory roles for Chugai Pharmaceutical. KU has received honoraria from Ono Pharmaceutical, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, AstraZeneca, Boehringer-Ingelheim, and had consulting/advisory roles for AstraZeneca, Chugai Pharmaceutical. SK has received honoraria from Chugai Pharmaceutical Co., Ltd., MSD K.K., Bristol-Myers Squibb, ONO Pharmaceutical, AstraZeneca. All the other Authors report no conflict of interest.
- Received February 9, 2021.
- Revision received February 18, 2021.
- Accepted February 19, 2021.
- Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
